Project Summary/Abstract UCSF Center for Synthetic Immunology: Tools to Reprogram the Immune System to Combat Cancer The immune system has emerged as an extraordinarily powerful tool for combating cancer. One of the most potent agents are engineered T cells programmed to recognize and kill tumor cells. Nonetheless, our ability to engineer T cells and other immune cells and program them to execute new functions remains relatively primitive. Aside from CAR T cells for treatment of blood cancers, most engineered cell therapies are risky, potentially highly toxic, unreliable and often ineffective, especially those cell therapies that attempt to target solid cancers. We hypothesize that to fulfil the promise of engineered immune cell therapies, we must first transform cell engineering into a systematic and predictable process; one that uses reliable technology platforms and principles. Our center will focus on developing a set of sophisticated immune engineering platforms that address three major needs in next-generation cell therapies: 1) Smart recognition of cancer ? develop antigen-pattern recognition circuits that direct immune cells to optimally recognize solid tumors and discriminate against normal tissue crossreaction, guided by computational bioinformatic analysis of gene expression patterns. 2) Overcoming the tumor microenvironment ? develop multiple classes of cellular circuits that can overcome or locally remodel immune-suppressive tumor microenvironments to promote highly efficient therapeutic immune cell trafficking, proliferation, persistence, and tumor-killing activity 3) User-control and safety ? to increase control over and safety of these powerful engineered cells, we will develop a suite of ways to communicate with and control the activity of engineered immune cells in vivo, including nano/microparticles and small molecules. To achieve these goals, we have assembled the UCSF Center for Synthetic Immunology, a tightly integrated interdisciplinary team that encompasses synthetic biologists, immunologists, bio-informaticists, control engineers, and materials scientists. The products of this center will include publicly available toolkits of parts and circuits for cell engineering, high-throughput platforms for rapid circuit assembly, new programmable nanomaterials for controlling immune cell behavior, searchable bioinformatic databases for optimization of tumor recognition, and computational frameworks for circuit design and for modeling/prototyping in vivo circuit function. These platforms will help to advance immune cell engineering to be far more reliable, predictable, effective and safe.